The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm

被引:294
作者
Zhao, L
Moos, MPW
Gräbner, R
Pédrono, F
Fan, JJ
Kaiser, B
John, N
Schmidt, S
Spanbroek, R
Lötzer, J
Huang, L
Cui, JS
Rader, DJ
Evans, JF
Habenicht, AJR
Funk, CD [1 ]
机构
[1] Univ Penn, Ctr Expt Therapeut, Philadelphia, PA 19104 USA
[2] Univ Jena, Inst Vasc Med, D-07743 Jena, Germany
[3] Queens Univ, Dept Physiol, Kingston, ON K7L 3N6, Canada
[4] Queens Univ, Dept Biochem, Kingston, ON K7L 3N6, Canada
[5] Merck & Co Inc, Dept Cardiovasc Dis, Rahway, NJ 07065 USA
[6] Univ Penn, Dept Med, Philadelphia, PA 19104 USA
[7] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA
关键词
D O I
10.1038/nm1099
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of proinflammatory leukotriene lipid mediators. Genetic studies have associated 5-LO and its accessory protein, 5-LO-activating protein, with cardiovascular disease, myocardial infarction and stroke. Here we show that 5-LO-positive macrophages localize to the adventitia of diseased mouse and human arteries in areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in mice deficient in apolipoprotein E. 5-LO deficiency markedly attenuates the formation of these aneurysms and is associated with reduced matrix metalloproteinase-2 activity and diminished plasma macrophage inflammatory protein-1alpha (MIP-1alpha; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulates expression of MIP-1alpha in macrophages and MIP-2 (also called CXCL2) in endothelial cells. These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route.
引用
收藏
页码:966 / 973
页数:8
相关论文
共 51 条
[1]   Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice [J].
Aiello, RJ ;
Bourassa, PA ;
Lindsey, S ;
Weng, WF ;
Freeman, A ;
Showell, HJ .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2002, 22 (03) :443-449
[2]   Interleukin-8 production by macrophages from atheromatous plaques [J].
Apostolopoulos, J ;
Davenport, P ;
Tipping, PG .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1996, 16 (08) :1007-1012
[3]   Chemokines and leukocyte traffic [J].
Baggiolini, M .
NATURE, 1998, 392 (6676) :565-568
[4]   Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors [J].
Basso, K ;
Liso, A ;
Tiacci, E ;
Benedetti, R ;
Pulsoni, A ;
Foa, R ;
Di Raimondo, F ;
Ambrosetti, A ;
Califano, A ;
Klein, U ;
Favera, RD ;
Falini, B .
JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (01) :59-68
[5]   A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice [J].
Boisvert, WA ;
Santiago, R ;
Curtiss, LK ;
Terkeltaub, RA .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :353-363
[6]   Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice [J].
Bruemmer, D ;
Collins, AR ;
Noh, G ;
Wang, W ;
Territo, M ;
Arias-Magallona, S ;
Fishbein, MC ;
Blaschke, F ;
Kintscher, U ;
Graf, K ;
Law, RE ;
Hsueh, WA .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (09) :1318-1331
[7]   CDNA CLONING, EXPRESSION, MUTAGENESIS, INTRACELLULAR-LOCALIZATION, AND GENE CHROMOSOMAL ASSIGNMENT OF MOUSE 5-LIPOXYGENASE [J].
CHEN, XS ;
NAUMANN, TA ;
KURRE, U ;
JENKINS, NA ;
COPELAND, NG ;
FUNK, CD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (30) :17993-17999
[8]   ROLE OF LEUKOTRIENES REVEALED BY TARGETED DISRUPTION OF THE 5-LIPOXYGENASE GENE [J].
CHEN, XS ;
SHELLER, JR ;
JOHNSON, EN ;
FUNK, CD .
NATURE, 1994, 372 (6502) :179-182
[9]   Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice [J].
Cyrus, T ;
Sung, S ;
Zhao, L ;
Funk, CD ;
Tang, S ;
Praticò, D .
CIRCULATION, 2002, 106 (10) :1282-1287
[10]   Mouse models of abdominal aortic aneurysms [J].
Daugherty, A ;
Cassis, LA .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (03) :429-434